P16 CDKN2 AND CDK4 GENE-MUTATIONS IN SPORADIC MELANOMA DEVELOPMENT AND PROGRESSION/

The p16/CDKN2 (MTSI) gene encoding for the p 16 inhibitor of cyclin D/ CDK4 complexes is frequently mutated and deleted in a large fraction o f melanoma cell lines, and p16 germline mutations have also been obser ved in familiar melanomas, Moreover, a CDK4 gene mutation, responsible for a functional resistance of CDK4 kinase to p16 inhibitory activity , has been described to occur in some cases of familial melanoma. Thes e data strongly support the idea that deregulation of the CDK4/cyclin D pathway, via CDKN2 or CDK4 mutations, is of biological significance in the development of melanoma. To shed light on the role of these alt erations in the development and progression of sporadic melanoma, 12 p rimary melanomas and 9 corresponding metastases were analyzed for CDKN 2 and CDK4 gene mutations. Of the 12 primary melanomas analyzed, 4 sho wed the presence of mutational inactivation of the p16 protein and 2 c arried silent mutations. No metastases showed the presence of CDKN2 mu tations, indicating that mutations of this cyclin-dependent kinase inh ibitor is not common in the progression of sporadic melanoma. On the o ther hand, the absence, in the metastases, of the CDKN2 mutation detec ted in the corresponding primary tumors suggests that 9p21 homozygous deletion may play a major role in the metastatic spreading of this typ e of tumor. None of the cases analyzed showed the presence of an Arg24 Cys mutation, which functionally protects CDK4 from p16 inhibition. Th is indicates that CDK4 mutation plays a minor role in the development and progression of sporadic melanoma. (C) 1997 Wiley-Liss. Inc,.